The efficiency of gene therapy strategies against cancer is limited by the poor distribution of the vectors in the malignant tissues. To solve this problem, a new generation of tumor-specific, conditionally replicative adenoviruses is being developed. To direct the replication of the virus to breast cancer, we have considered one characteristic present in a great proportion of these cancers, which is the expression of estrogen receptors (ERs). On the basis of the wild-type adenovirus type 5, we have constructed a conditionally replicative adenovirus (Ad5ERE2) in which the E1a and E4 promoters have been replaced by a portion of the pS2 promoter containing two estrogen-responsive elements (EREs). This promoter induces transcriptional activation of the E1a and E4 units in response to estrogens in cells that express the ERs. Ad5ERE2 is able to kill ER(+) human breast cancer cell lines as efficiently as the wild-type virus, but has decreased capacity to affect ER(-) cells. By complementation of the E1a protein in trans, Ad5ERE2 allows restricted replication of a conventional E1a-deleted adenoviral vector. When a virus expressing the proapoptotic gene Bc1-xs (Clarke et al., Proc. Natl. Acad. Sci. U.S.A. 1995;92:11024-11028) is used in combination with Ad5ERE2, the ability of both viruses to induce cell death is dramatically increased, and the effect can be modulated by addition of the antiestrogen tamoxifen.

BACKGROUND: Approximately 50% of postmenopausal women with hormone receptor-positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI-associated musculoskeletal symptoms. METHODS: The authors performed a single-arm, open-label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data. RESULTS: Twenty-one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol-directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%-73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0-72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache. CONCLUSIONS: Duloxetine appears to be effective and well tolerated for treatment of AI-associated musculoskeletal symptoms. Future randomized, placebo-controlled studies are warranted. Cancer 2011;117:5469-

The value of chimeric antigen receptor-modified donor lymphocyte infusion (CAR-DLI) is unclear in B-cell acute lymphoblastic leukemia (B-ALL), particularly in patients with relapsed diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, 5 B-ALL patients who relapsed after allo-HSCT received CAR-DLI (CAR-DLI group), and the outcome was compared with 27 relapsed B-ALL patients who received DLI therapy (DLI group). The median complete remission duration of CAR-DLI group was significantly (P = 0.020) longer when compared with DLI group: 9 months (range, 2-29) versus 3.2 months (range, 0-17.4). Furthermore, patients receiving CAR-DLI showed significant (P = 0.049) survival advantage over DLI group, with median overall survival of 12 months (range, 3-29) and 3.7 months (range, 0-65), respectively. Of note, no patient developed acute graft versus host disease in the CAR-DLI group, while incidence of acute graft versus host disease grades I-II and grades III-IV were 2 (7%) and 4 (14.8%) in the DLI group, respectively. In addition, cytokine release syndrome in CAR-DLI group was manageable. Overall, our study demonstrated that CAR-DLI significantly improved the survival of B-ALL patients relapsed after allo-HSCT, thus indicating that CAR-DLI may represent an alternative and more effective therapy for B-ALL patients with relapsed diseases.

Background: Approximately 50% of postmenopausal women with hormone receptor positive early stage breast cancer treated with an aromatase inhibitor (AI) develop arthralgias. Standard analgesics are relatively ineffective. Duloxetine is a serotonin and norepinephrine receptor inhibitor with proven efficacy for treatment of multiple chronic pain states. We investigated the hypothesis that duloxetine would be efficacious for treatment of AIMSS. Methods: We performed a single-arm, open-label phase II study of duloxetine in 35 postmenopausal women who had been treated with AI therapy for at least 2 weeks and who developed new or worsening pain after starting AI therapy that was rated at least 4 on a 10 point Visual Analog Scale. Enrollment was completed in June 2010. Subjects were treated with duloxetine 30 mg daily for one week, and then 60 mg daily for 3 weeks. Depending on patient-perceived response to therapy, patients had the option of continuing duloxetine 60 mg daily or increasing the dose to 60 mg twice daily for the subsequent 4 weeks. Change in patient-reported pain was assessed. Outcome measures included the Brief Pain Inventory (BPI) and modified Health Assessment Questionnaire (HAQ). Benefit from therapy was defined as a 30% decrease in average pain score from baseline to 8 weeks. Paired t tests were used for statistical analysis. Results: Of the 35 enrolled subjects, 20 subjects completed the 8-week study period, 6 subjects discontinued therapy early because of duloxetine-associated toxicity, and 9 subjects had been enrolled less than 8 weeks at the time of this analysis and were therefore not evaluable. In an intent-to-treat analysis, 16 of 26 evaluable subjects (61.5%) experienced at least a 30% decrease in average pain, and 14 of 20 subjects (70%) who completed all 8 weeks of protocol-directed treatment chose to continue duloxetine therapy. There were statistically significant reductions in average pain severity (p < 0.0001) and maximum pain severity (p < 0.0001) from baseline to 8 weeks. The mean percent reduction in average pain severity between baseline and 8 weeks was 56.1% (95% CI 37.9%-74.2%) and in maximum pain severity was 55.7% (95% CI 37.3%-74.1%). No grade 3 or 4 adverse events were reported. The most common adverse events were fatigue and drowsiness, xerostomia, nausea, and headache. Conclusions: Duloxetine appears to be effective and well-tolerated for treatment of AIMSS. Final results from the entire cohort will be presented. Future randomized, placebo-controlled studies are warranted. Clinicaltrials. gov NCT01028352. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD08-06.